Human surgery, and especially oncologic surgery, is in need of improved image-guidance. Presently, surgery is performed "blindly," without visual cues for tissue that needs to be removed (e.g., cancer), tissue that needs to be avoided (e.g., nerves), or otherwise healthy tissue that is becoming inadvertently ischemic during the procedure (e.g., from clamping). As part of a Bioengineering Research Partnership, the PI's laboratory has developed a near-infrared (NIR) fluorescence imaging system that utilizes exogenous fluorophores and invisible NIR light to help guide surgery. The imaging system uses continuous wave (CW) excitation and simple reflectance optics, and is now entering clinical trials. Although likely to find utility in many types of surgery, the present imaging system produces only qualitative information, and is unable to reconstruct, quantitatively, the absorbing (i.e., [unreadable]A) and scattering (i.e., [unreadable]S') properties of living tissue, and fluorophore quantum yield (QY). Such information will have immediate clinical impact since it will, for the first time, permit non-invasive, image-based assessment of tissue oxygenation, and will greatly improve NIR fluorophore sensitivity by reducing autofluorescence. In this application, we propose the use of spatially-modulated NIR light (SMNL) to produce quantitative imaging of [unreadable]A, [unreadable]S', and QY in essentially real-time. Our collaborator, the Tromberg group at the Beckman Laser Institute of the University of California, Irvine, has pioneered the use of this technology for quantitative, depth-resolved spectroscopic imaging as part of the Laser Microbeam and Medical Program (LAMMP) at the Beckman Laser Institute (www.bli.uci.edu/lammp). Recent results shown in Preliminary Studies suggest that SMNL can now be optimized for use over a large surgical field without the need for a laser excitation source. When combined with a novel LED-based light source proposed in this study, and recent advances in cardiac and respiratory gating technology from the PI's laboratory, SMNL should be able to provide surgeons with direct measurement of [unreadable]A, [unreadable]S', and QY, and thus improve virtually all image-guided surgical interventions. Phase I of this project leverages the complementary expertise of two imaging groups, and uses "collaborative feedback," to rapidly optimize the performance of a novel clinical imaging system. The Specific Aims are focused on the mathematical modeling of those SMNL acquisition parameters and performance metrics required for human surgery;the engineering of a novel, LED-based light source capable of projecting multi-wavelength, high fluence rate patterned light over a 15 cm diameter FoV;and the optimization of the technology for real-time imaging using large animal surgical models. Successful completion of the Specific Aims and Milestones will ensure that this new technology for image-guided interventions is translated efficiently to the clinic during project Phase II. 7. PROJECT NARRATIVE Human surgery, and especially oncologic surgery, is in need of improved image-guidance. Presently, surgery is performed "blindly," without visual cues for tissue that needs to be removed, tissue that needs to be avoided, or otherwise healthy tissue that is becoming inadvertently injured during the procedure. Successful completion of the specific aims in this application will ensure that a novel optical imaging technology for image-guided surgical interventions is translated efficiently to the clinic.